Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylate metabolism, arises from mutations in the enzyme alanine-glyoxylate aminotransferase. The resulting deficiency in this ...enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other tissues, with systemic oxalosis and ESRD being a common outcome. Although a small subset of patients manages the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant, which requires life-long immune suppression and carries significant mortality risk. In this report, we discuss the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis. Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and nonhuman primates. ALN-GO1 also increased urinary glycolate concentrations in normal nonhuman primates and in a genetic mouse model of PH1. Notably, ALN-GO1 reduced urinary oxalate concentration up to 50% after a single dose in the genetic mouse model of PH1, and up to 98% after multiple doses in a rat model of hyperoxaluria. These data demonstrate the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and provide a clear rationale for clinical trials with this compound.
In order to meet the fast and accurate automatic detection requirements of equipment maintenance in railway tunnels in the era of high-speed railways, as well as adapting to the high dynamic, ...low-illumination imaging environment formed by strong light at the tunnel exit, we propose an automatic inspection solution based on panoramic imaging and object recognition with deep learning. We installed a hyperboloid catadioptric panoramic imaging system on an inspection vehicle to obtain a large field of view as well as to shield the high dynamic phenomena at the tunnel exit, and proposed a YOLOv5-CCFE object detection model based on railway equipment recognition. The experimental results show that the mAP@0.5 value of the YOLOv5-CCFE model reaches 98.6%, and mAP@0.5:0.95 reaches 68.9%. The FPS value is 158, which can meet the automatic inspection requirements of railway tunnel equipment along the line and has high practical application value.
Seed germination is a critical and complex process in the plant life cycle. Although previous studies have found that melatonin can promote seed germination under salt stress, the involvement of ...melatonin in the regulation of proteomic changes remains poorly understood. In this study, a total of 157 proteins were significantly influenced (ratio ≥ 2 or ≤ -2) by melatonin during seed germination under salt stress using a label-free quantitative technique. Our GO analysis revealed that several pathways were obviously regulated by melatonin, including ribosome biosynthesis, lipid metabolism, carbohydrate metabolism, and storage protein degradation. Not only stress-tolerant proteins but also proteins that produce ATP as part of glycolysis, the citric acid cycle, and the glyoxylate cycle were upregulated by melatonin. Overall, this study provides new evidence that melatonin alleviates the inhibitory effects of NaCl stress on seed germination by promoting energy production. This study is the first to provide insights at the proteomic level into the molecular mechanism of melatonin in response to salt stress in cucumber seeds. This may be helpful to further understand the role of melatonin in cucumber seed germination under stress conditions.
In this work, we found, that exogenous melatonin pretreatment improved anthocyanin accumulation (1- to 2-fold) in cabbage. To verify the relationship with melatonin and anthocyanin, an Arabidopsis ...mutant, snat, which expresses a defective form of the melatonin biosynthesis enzyme SNAT (Serotonin N-acetyl transferase), was employed. Under cold conditions, the foliage of wild-type Arabidopsis exhibited a deeper red color than the snat mutant. This finding further proved, that exogenous melatonin treatment was able to affect anthocyanin accumulation. To gain a better understanding of how exogenous melatonin upregulates anthocyanin, we measured gene expression in cabbage samples treated with melatonin and untreated controls. We found that the transcript levels of anthocyanin biosynthetic genes were upregulated by melatonin treatment. Moreover, melatonin treatment increased the expression levels of the transcription factors MYB, bHLH, and WD40, which constitute the transcriptional activation complex responsible for coordinative regulation of anthocyanin biosynthetic genes. We found, that free radical generation was downregulated, whereas the osmotic adjustment and antioxidant capacities were upregulated in exogenous melatonin-treated cabbage plants. We concluded, that melatonin increases anthocyanin production and benefits cabbage growth.
Serum gamma-glutamyltransferase (GGT) elevation likely contributes to cardiovascular (CV) mortality, however it has remained unknown whether a dose-response relationship exists between serum GGT and ...CV mortality.
We searched the PubMed, EMBASE, and Cochrane library databases for prospective cohort studies published up to October 2, 2016. Summary hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were calculated using a fixed effects model.
Nine prospective studies, including 527,589 participants and more than 7,011 cases, were included in this meta-analysis. For the moderate, high, and highest levels of GGT, the pooled HRs of CV mortality were 1.11 (95% CI = 1.04-1.19), 1.29 (95% CI = 1.21-1.38) and 1.59 (95% CI = 1.47-1.72), respectively (all p < 0.05 as compared to the lowest levels of GGT). Additionally, the HR per incremental increase of GGT by 10 U/L was 1.10 (95% CI = 1.08-1.11). Evidence of a positive relationship with nonlinear trend for GGT elevation with CV mortality in females was found (P = 0.04 for nonlinearity). However, a linear model was better fit to illustrate the GGT-CV mortality among males (P = 0.304 for nonlinearity).
These findings indicate that serum GGT activity within the reference interval is positively associated with increased risk of CV mortality in a dose-response manner.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
Ultrasound (US) technology has recently made advances that have led to the development of modalities including elastography and contrast-enhanced ultrasound. The use of different US ...modalities in combination may increase the accuracy of PCa diagnosis. This study aims to assess the diagnostic accuracy of multiparametric ultrasound (mpUS) in the PCa diagnosis.
Methods
Through September 2023, we searched through Cochrane CENTRAL, PubMed, Embase, Scopus, Web of Science, ClinicalTrial.gov, and Google Scholar for relevant studies. We used standard methods recommended for meta-analyses of diagnostic evaluation. We plot the SROC curve, which stands for summary receiver operating characteristic. To determine how confounding factors affected the results, meta-regression analysis was used.
Results
Finally, 1004 patients from 8 studies that were included in this research were examined. The diagnostic odds ratio for PCa was 20 (95% confidence interval (CI), 8–49) and the pooled estimates of mpUS for diagnosis were as follows: sensitivity, 0.88 (95% CI, 0.81–0.93); specificity, 0.72 (95% CI, 0.59–0.83); positive predictive value, 0.75 (95% CI, 0.63–0.87); and negative predictive value, 0.82 (95% CI, 0.71–0.93). The area under the SROC curve was 0.89 (95% CI, 0.86–0.92). There was a significant heterogeneity among the studies (
p
< 0.01). According to meta-regression, both the sensitivity and specificity of mpUS in the diagnosis of clinically significant PCa (csPCa) were inferior to any PCa.
Conclusion
The diagnostic accuracy of mpUS in the diagnosis of PCa is moderate, but the accuracy in the diagnosis of csPCa is significantly lower than any PCa. More relevant research is needed in the future.
Critical relevance statement
This study provides urologists and sonographers with useful data by summarizing the accuracy of multiparametric ultrasound in the detection of prostate cancer.
Key points
• Recent studies focused on the role of multiparametric ultrasound in the diagnosis of prostate cancer.
• This meta-analysis revealed that multiparametric ultrasound has moderate diagnostic accuracy for prostate cancer.
• The diagnostic accuracy of multiparametric ultrasound in the diagnosis of clinically significant prostate cancer is significantly lower than any prostate cancer.
Graphical Abstract
The biomacromolecule silk fibroin (SF) may be constructed to promote biomimetic nucleation and nanostructures of inorganic nanomaterials, offering it a promising candidate for use in various ...biomimetic applications. We combined SF-NPs and ZIF-8-NPs to fabricate new drug vehicles that effectively release the drug. SF nanoparticles (SF-NPs) were assembled into quercetin (QCT), a myocardial drug added to fabricate QSF-NPs. By acting as a template for the ZIF-8 nucleation onto the surface, the QSF-NPs fabricated core-shell-structured nanocomposites (named QSF@Z-NCs) with ZIF-8 as the core-shell and the QSF-NPs. The biocompatibility analysis using the MTT assay revealed that the developed QCT, SF-NPs, and QSF@Z-NCs are not harmful to cardiac myoblast (H9C2) cells. The in vivo model demonstrated that H9C2 cells encouraged cardiomyocyte fibre regeneration in myocardial infarction rats. We fabricated a brand-new technique using H9C2 cells and QSF@Z-NCs that might encourage the healing processes in myocardial ischemia cells. This study's results demonstrate that it successfully treats myocardial injury.
TLPs (Tubby-like proteins) are widespread in eukaryotes and highly conserved in plants and animals. TLP is involved in many biological processes, such as growth, development, biotic and abiotic ...stress responses, while the underlying molecular mechanism remains largely unknown. In this paper we characterized the biological function of cucumber (Cucumis sativus L.) Tubby-like protein 8 (CsTLP8) in Arabidopsis. In cucumber, the expression of the tubby-like protein CsTLP8 was induced by NaCl treatment, but reduced by PEG (Polyethylene Glycol) and ABA (Abscisic Acid) treatment. Subcellular localization and transcriptional activation activity analysis revealed that CsTLP8 possessed two characteristics of classical transcription factors: nuclear localization and trans-activation activity. Yeast two-hybrid assay revealed interactions of CsTLP8 with CsSKP1a and CsSKP1c, suggesting that CsTLP8 might function as a subunit of E3 ubiquitin ligase. The growth activity of yeast with ectopically expressed CsTLP8 was lower than the control under NaCl and mannitol treatments. Under osmotic and salt stresses, overexpression of CsTLP8 inhibited seed germination and the growth of Arabidopsis seedlings, increased the content of MDA (Malondialdehyde), and decreased the activities of SOD (Superoxide Dismutase), POD (Peroxidase) and CAT (Catalase) in Arabidopsis seedlings. Overexpression of CsTLP8 also increased the sensitivity to ABA during seed germination and ABA-mediated stomatal closure. Under osmotic stress, CsTLP8 might inhibit seed germination and seedling growth by affecting antioxidant enzymes activities. CsTLP8 acts as a negative regulator in osmotic stress and its effects may be related to ABA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in the cerebrovascular endothelium is a key suppressor of post-stroke brain damage. However, the role of PPARγ's co-regulators ...during cerebral ischemia remains largely unknown. Here, we show that the transcription factor IRF6 is a novel PPARγ co-regulator that directly binds to and suppresses PPARγ activity in murine cerebrovascular endothelial cells. Moreover, IRF6 was also revealed to be a transcriptional target of PPARγ suppression, with PPARγ silencing significantly promoting IRF6 expression in cerebrovascular endothelial cells. In addition, IRF6 silencing significantly promoted pioglitazone's cytoprotective effects in ischemic murine cerebrovascular endothelial cells. Mechanistically, IRF6 significantly suppressed PPARγ's transcriptional inhibition of the ischemia-induced, pro-apoptotic microRNA miR-106a. In conclusion, we identified IRF6 as a novel PPARγ co-suppressor that serves a key role in suppressing PPARγ-mediated cerebrovascular endothelial cytoprotection following ischemia. Further investigation into IRF6 and other PPARγ co-regulators should provide additional insights into PPARγ's cytoprotective role in the cerebrovascular endothelium following stroke.
PDF
